Since its initial description in 1994, Kaposi's sarcoma associated herpesvirus (KSHV), or HHV-8, has assumed prominence as a viral infection of international public health importance, especially for persons with HIV and other immunosuppressive conditions. The incidence of HHV-8 infection is on the rise, particularly in children in underdeveloped countries, which draws attention to the mode of transmission that until recently was thought to be by intimate sexual contact. In a series of studies, we have demonstrated that HHV-8 DNA is detected ten times more frequently in oropharyngeal than anogenital secretions, and that titers of HHV-8 in oropharyngeal swabs and saliva are two to three logs higher than those found in semen, prostatic secretions, or anal/rectal swabs. Unlike genital secretions, saliva contains virion HHV-8, suggesting direct contact with oral secretions may be important for viral transmission. The precise anatomic site(s) of latent and lytic HHV-8 replication, and factors that determine the frequency and concentration of HHV-8 virions in saliva are not known. Our preliminary data suggests that the frequency of HHV-8 shedding in saliva is increased in the presence of HIV infection, with lingual and tonsil swabs demonstrating the highest viral titers. Salivary glands do not appear to be a significant source of HHV-8. However, this requires further investigation. A preliminary study, in which we obtained tonsil specimens from two HHV-8/HIV seropositive men, demonstrated infection of germinal center B cells in areas of HIV p24 antigen expression. HHV-8 lytic gene transcripts in these biopsies localize to epithelial cells extending from the lymphoepithelial junction to the capsular surface. In vitro studies using a recombinant HHV-8 containing the gene that encodes the green fluorescent protein have shown that primary oral keratinocytes support virus replication. We have also shown that B lymphocytes derived from tonsils are highly permissive to HHV-8 infection and lytic gene expression which can be induced by adding supernatants from HIV-infected cell lines. Which HIV proteins and the precise nature of these co-viral interactions are yet to be determined. These results of these studies will improve our understanding of HHV-8 pathogenesis and ultimately will enable us to propose more rational prevention strategies. This award will support the pursuit of my long-term career goal, which is to become a proficient independent clinical investigator focusing on infections in the immunocompromised host.